Inhibitor Report for: GV

1 The toxicity of pinacolyl methylphosphonofluoridate (soman, GD), cyclohexyl methylphosphonofluoridate (cyclohe xylsarin, GF) and 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV) and the therapeutic efficacy of two oximes (obidoxime and HI-6) in combination with atropine against mentioned nerve agents were evaluated in mice. 2 The 24-h i.m. LD50 of GD was 101 micrograms/kg (99.5-104.0), LD50 of GF was 170 micrograms/kg (151.0-190.0 and LD50 of GV was 25.2 micrograms/kg (23.0-27.7). 3 The efficacy of two oximes, obidoxime (15 and 30 mg/kg) or HI-6 (15 and 30 mg/kg) in combination with atropine (21 mg/kg) was tested. HI-6 was significantly more effective in reducing mortality than obidoxime following poisoning with all three nerve agents. 4 Higher doses of both oximes showed significantly more effective therapeutic efficacy against all nerve agents studied.

In experiments on male rats, the effect of selected cholinolytic agents (atropine, benactyzine, G 3063) in combination with the reactivator of cholinesterases HI-6 on the cholinergic and non-cholinergic effects of GV substance in the course of acute sublethal intoxication was compared. The cholinergic affects of GV substance were examined by means of the changes in the activity of cholinesterases in whole blood, the CNS, diaphragm and liver, the noncholinergic stressogenic effects by means of the changes in the level of corticosterone in plasma and the activity of tyrosine amino transferase in the liver. It follows from the changes in the activity of cholinesterases that the cholinergic effects of GV substance are least influenced by atropine, whereas benactyzine and G 3063 exert an approximately similar effect. The difference in the effect is evident especially in the 24th hour of intoxication. Similarly stressogenic effects of GV substance are least influenced by an antidotal combination of atropine and HI-6. It means that the centrally acting cholinolytic agents benactyzine and G 3063 are more advantageous for the therapy of GV substance poisonings than the peripherally acting atropine.

Acetylcholinesterase activity in the blood, pontomedullar area, basal ganglia of the brain and diaphragm following sublethal soman (i.m., 31 micrograms/kg) and 2-dimethylaminoethyl-(dimethylamido)-fluorophosphate (GV) poisoning (i.m., 6 micrograms/kg) was studied in groups of rats (n = 6) pretreated as follows: intact, hepatectomized, sham-operated and narcotized animals. Except hepatectomized rats, all animals in the groups survived; in hepatectomized rats, 2 animals died following soman poisoning. Acetylcholinesterase activity was decreased in each group. The highest and significant (p < 0.05-0.0001) decrease of this activity in the pontomedullar area and diaphragm following hepatectomy was demonstrated. The results indicate that undiminished liver functional capacity is an important factor influencing soman and GV anticholinesterase action.

1 The toxicity of pinacolyl methylphosphonofluoridate (soman, GD), cyclohexyl methylphosphonofluoridate (cyclohe xylsarin, GF) and 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV) and the therapeutic efficacy of two oximes (obidoxime and HI-6) in combination with atropine against mentioned nerve agents were evaluated in mice. 2 The 24-h i.m. LD50 of GD was 101 micrograms/kg (99.5-104.0), LD50 of GF was 170 micrograms/kg (151.0-190.0 and LD50 of GV was 25.2 micrograms/kg (23.0-27.7). 3 The efficacy of two oximes, obidoxime (15 and 30 mg/kg) or HI-6 (15 and 30 mg/kg) in combination with atropine (21 mg/kg) was tested. HI-6 was significantly more effective in reducing mortality than obidoxime following poisoning with all three nerve agents. 4 Higher doses of both oximes showed significantly more effective therapeutic efficacy against all nerve agents studied.

Changes of some physiological functions in rats were studied following intoxication with new type of highly toxic organophosphate GV [2-dimethylaminoethyl-(dimethylamido)-fluorophosphate] in doses of 2x and 4x LD50 i.m. The intoxication has begun with increasing motoric activity followed by increased salivation, rumination and bristling. Tachypnoe and fasciculations followed by convulsions and death were observed later. Therapy of intoxication with GV compound (in dose of 2x LD50) in rats demonstrated the best antidotal effect of combination of benactyzine, atropine and HI-6. In GV intoxication in higher doses (4x LD50), therapeutic efficacy (survival of experimental animals) was limited for 24 hours. HI-6 can be therefore considered as potentially universal reactivator for the treatment of nerve agents intoxication.

In experiments on male rats, the effect of selected cholinolytic agents (atropine, benactyzine, G 3063) in combination with the reactivator of cholinesterases HI-6 on the cholinergic and non-cholinergic effects of GV substance in the course of acute sublethal intoxication was compared. The cholinergic affects of GV substance were examined by means of the changes in the activity of cholinesterases in whole blood, the CNS, diaphragm and liver, the noncholinergic stressogenic effects by means of the changes in the level of corticosterone in plasma and the activity of tyrosine amino transferase in the liver. It follows from the changes in the activity of cholinesterases that the cholinergic effects of GV substance are least influenced by atropine, whereas benactyzine and G 3063 exert an approximately similar effect. The difference in the effect is evident especially in the 24th hour of intoxication. Similarly stressogenic effects of GV substance are least influenced by an antidotal combination of atropine and HI-6. It means that the centrally acting cholinolytic agents benactyzine and G 3063 are more advantageous for the therapy of GV substance poisonings than the peripherally acting atropine.

Acetylcholinesterase activity in the blood, pontomedullar area, basal ganglia of the brain and diaphragm following sublethal soman (i.m., 31 micrograms/kg) and 2-dimethylaminoethyl-(dimethylamido)-fluorophosphate (GV) poisoning (i.m., 6 micrograms/kg) was studied in groups of rats (n = 6) pretreated as follows: intact, hepatectomized, sham-operated and narcotized animals. Except hepatectomized rats, all animals in the groups survived; in hepatectomized rats, 2 animals died following soman poisoning. Acetylcholinesterase activity was decreased in each group. The highest and significant (p < 0.05-0.0001) decrease of this activity in the pontomedullar area and diaphragm following hepatectomy was demonstrated. The results indicate that undiminished liver functional capacity is an important factor influencing soman and GV anticholinesterase action.